title: Investigations on synthesis and structure elucidation of novel [1,2,4]triazolo[1,2-a]pyridazine-1-thiones and their inhibitory activity against inducible nitric oxide synthase.
abstract: The inducible nitric oxide synthase (iNOS) is a target of great research interest due to its importance in a number of diseases, for example, septic shock and inflammatory lung diseases. A variety of 3-substituted [1,2,4]triazolo[1,2-a]pyridazine derivatives was synthesized by ring closure with hexahydropyridazine-1-carbothioamide by using aliphatic and aromatic aldehydes. The activity of the new substances was tested on the insulin-secreting rat insulinoma cell line RINm5F. iNOS was expressed through exposure to interleukin-1β (IL-1β) and interferon-γ (IFN-γ). A number of the investigated compounds were more active than the reference inhibitor aminoguanidine (AG). Structure-activity relationships showed that a phenyl substituent in position 3 is apparently essential for inhibition.
authors.affiliation: Institute of Pharmacy, Ernst Moritz Arndt University Greifswald, Friedrich-Ludwig-Jahn-Straße 17, 17487 Greifswald, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schulz
authors.forename: Antje
authors.initials: A
authors.lastname: Grossmann
authors.forename: Manja
authors.initials: M
authors.lastname: Witetschek
authors.forename: Christian
authors.initials: C
authors.lastname: Lemmerhirt
authors.forename: Marcus
authors.initials: M
authors.lastname: Polzin
authors.forename: Beate
authors.initials: B
authors.lastname: Haertel
authors.forename: Heike
authors.initials: H
authors.lastname: Wanka
authors.forename: Olaf
authors.initials: O
authors.lastname: Morgenstern
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011724:Pyridazines / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D011724:Pyridazines; D013871:Thiones; D014230:Triazoles; D009569:Nitric Oxide; C062482:pyridazine; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II
keywords: Hexahydropyridazine-1-carbothioamide; Inducible nitric oxide synthase; RINm5F; [1,2,4]Triazolo[1,2-a]pyridazine-1-thiones